Understanding cognitive deficits in Parkinson’s disease: lessons from preclinical animal models

Abstract

Parkinson's disease (PD) has been, until recently, mainly defined by the presence of characteristic motor symptoms, such as rigidity, tremor, bradykinesia/akinesia, and postural instability. Accordingly, pharmacological and surgical treatments have so far addressed these motor disturbances, leaving nonmotor, cognitive deficits an unmet clinical condition. At the preclinical level, the large majority of studies aiming at defining mechanisms and testing novel therapies have similarly focused on the motor aspects of PD. Unfortunately, deterioration of the executive functions, such as attention, recognition, working memory, and problem solving, often appear in an early, premotor phase of the disease and progressively increase in intensity, negatively affecting the quality of life of 50% -60% of PD patients. At present, the cellular mechanisms underlying cognitive impairments in PD patients are largely unknown and an adequate treatment is still missing. The preclinical research has recently developed new animal models that may open new perspectives for a more integrated approach to the treatment of both motor and cognitive symptoms of the disease. This review will provide an overview on the cognitive symptoms occurring in early PD patients and then focus on the rodent and nonhuman primate models so far available for the study of discriminative and spatial memory attention and learning abilities related to this pathological condition. Cognitive deficits in Parkinson's diseaseParkinson's disease (PD) is a chronic neurodegenerative disorder affecting over four million people worldwide (Dorsey et al. 2007). It is classically characterized by the emergence of motor symptoms such as rigidity, tremor, postural unbalance, and bradykinesia/akinesia (Braak et al. 2003;Jankovic 2008). However, PD also involves nonmotor symptoms (NMS) (Chaudhuri et al. 2006;Jankovic 2008) that appear in the early, often premotor, phase of the disease (Abbott et al. 2005;Abbott 2007;Claassen et al. 2010) and significantly contribute to the impairment of the quality of life of 50%-60% of PD patients (Aarsland et al. 2012). Among others, NMS include olfactory dysfunction, REM sleep disorder, neuropsychiatric disturbances, and cognitive deficits (Schrag et al. 2004;Chaudhuri and Odin 2010). All these symptoms develop independently from each other in the early phase of the disease, and progressively increase in intensity, often leading to dementia in the late phase (Cools et al. 2001;Goetz et al. 2008).Neuropsychiatric mood-related disorders are rather common in PD (Cummings 1992;Schrag et al. 2004) with a prevalence of 20% (Reijnders et al. 2008), and manifest as apathy, depression, and anxiety.On the other hand, cognitive impairments associated with PD are mainly related to the executive functions, resulting in a phenotype resembling that of frontal lobe patients (Robbins and Arnsten 2009), with deficits in attention (Ballard et al. 2002), planning, concept formation, and working memory (Kehagia et al. 2010). In particular, memory deterioration aff...

Long-Term Treatment with Fluvoxamine Decreases Nonmotor Symptoms and Dopamine Depletion in a Postnatal Stress Rat Model of Parkinson’s Disease

“…Besides, given the hippocampus-dependent learning and memory, the long-lasting and elevated plasma corticosterone levels impaired learning and memory resulting in poor cognitive performance of maternally separated rats in the MWM test. This specific result agreed with previous studies and provided evidence that exposure to maternal separation impaired learning and memory in rats [32,[59][60][61][62][63].…”

Investigating the Effects of Tolcapone a Catechol-O-Methyltransferase Inhibitor on Learning and Memory in Passive Avoidance Task

“…Dopamine and its regulation play a crucial role in a great number of hippocampal functions, amongst which cognition, learning and memory processes [10]. There are preclinical experimental models which support the above mentioned by demonstrating that impaired behavioral and cognitive tasks are mediated by brain areas such as striatum but also hippocampus and prefrontal cortex [8].…”

“…Although the motor symptoms are linked to the progressive degeneration of dopaminergic neurons the pathogenesis of cognitive decline remains unclear [8]. One relatively recent clinical study suggests that cognitive deficiency might be explained with dopaminergic degeneration of SNpc as well as with the essential involvement of prefrontal cortex, hippocampus and amygdala [9].…”

Distinct genetic signatures of cortical and subcortical regions associated with human memory

“…Therefore, a key question stands: Do functionally distinct human cortical and subcortical memory regions [18][19][20][21] possess distinct genetic signatures associated with memory function? The answer could provide an insight into the underlying biological processes and genes underlying human cortical and subcortical memory, and benefit drug discovery for cognitive enhancement 22 and the treatment of memory disorders [23][24][25] .…”